6bfe: Difference between revisions
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<StructureSection load='6bfe' size='340' side='right' caption='[[6bfe]], [[Resolution|resolution]] 1.51Å' scene=''> | <StructureSection load='6bfe' size='340' side='right' caption='[[6bfe]], [[Resolution|resolution]] 1.51Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6bfe]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFE FirstGlance]. <br> | <table><tr><td colspan='2'>[[6bfe]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFE FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DJV:N-[(1R,2S)-1-[(2R,4R)-4-(cyclohexylmethoxy)pyrrolidin-2-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide'>DJV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DJV:N-[(1R,2S)-1-[(2R,4R)-4-(cyclohexylmethoxy)pyrrolidin-2-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide'>DJV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfe OCA], [http://pdbe.org/6bfe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfe RCSB], [http://www.ebi.ac.uk/pdbsum/6bfe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfe ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfe OCA], [http://pdbe.org/6bfe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfe RCSB], [http://www.ebi.ac.uk/pdbsum/6bfe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfe ProSAT]</span></td></tr> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Timm, D E]] | [[Category: Timm, D E]] | ||
Revision as of 12:00, 27 December 2017
BACE crystal structure with hydroxy pyrrolidine inhibitorBACE crystal structure with hydroxy pyrrolidine inhibitor
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedNMR Conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartyl protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1' and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogs, have been found to be brain penetrant BACE-1 inhibitors. Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.,Bueno AB, Agejas J, Broughton HB, Dally R, Durham T, Espinosa JF, Gonzalez R, Hahn PJ, Marcos A, Rodriguez R, Sanz G, Soriano J, Timm DE, Vidal P, Yang HC, McCarthy J J Med Chem. 2017 Oct 31. doi: 10.1021/acs.jmedchem.7b01304. PMID:29088532[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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